About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
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May 13, 2009

Exercise and Vitamins: Now, Wait A Minute. . .

Posted by Derek

Now, this is an example of an idea being followed through to its logical conclusion. Here’s where we start: the good effects of exercise are well known, and seem to be beyond argument. Among these are marked improvements in insulin resistance (the hallmark of type II diabetes) and glucose uptake. In fact, exercise, combined with losing adipose weight, is absolutely the best therapy for mild cases of adult-onset diabetes, and can truly reverse the condition, an effect no other treatment can match.

So, what actually causes these exercise effects? There has to be a signal (or set of signals) down at the molecular level that tells your cells what’s happening, and initiates changes in their metabolism. One good candidate is the formation of reactive oxygen species (ROS) in the mitochondria. Exercise most certainly increases a person’s use of oxygen, and increases the work load on the mitochondria (since that’s where all the biochemical energy is coming from, anyway). Increased mitochondrial formation of ROS has been well documented, and they have a lot of physiological effects.

Of course, ROS are also implicated in many theories of aging and cellular damage, which is why cells have several systems to try to soak these things up. That’s exactly why people take antioxidants, vitamin C and vitamin E especially. So. . .what if you take those while you’re exercising?

A new paper in PNAS askes that exact question. About forty healthy young male volunteers took part in the study, which involved four weeks of identical exercise programs. Half of the volunteers were already in athletic training, and half weren’t. Both groups were then split again, and half of each cohort took 1000 mg/day of vitamin C and 400 IU/day vitamin E, while the other half took no antioxidants at all. So, we have the effects of exercise, plus and minus previous training, and plus and minus antioxidants.

And as it turns out, antioxidant supplements appear to cancel out many of the beneficial effects of exercise. Soaking up those transient bursts of reactive oxygen species keeps them from signaling. Looked at the other way, oxidative stress could be a key to preventing type II diabetes. Glucose uptake and insulin sensitivity aren't affected by exercise if you're taking supplementary amounts of vitamins C and E, and this effect is seen all the way down to molecular markers such as the PPAR coactivator proteins PGC1 alpha and beta. In fact, this paper seems to constitute strong evidence that ROS are the key mediators for the effects of exercise, and that this process is mediated through PGC1 and PPAR-gamma. (Note that PPAR-gamma is the target of the glitazone class of drugs for type II diabetes, although signaling in this area is notoriously complex).

Interestingly, exercise also increases the body's endogenous antioxidant systems - superoxide dismutase and so on. These are some of the gene targets of PPAR-gamma, suggesting that these are downstream effects. Taking antioxidant supplements kept these from going up, too. All these effects were slightly more pronounced in the group that hadn't been exercising before, but were still very strong across the board.

This confirms the suspicions raised by a paper from a group in Valencia last year, which showed that vitamin C supplementation seemed to decrease the development of endurance capacity during an exercise program. I think that there's enough evidence to go ahead and say it: exercise and antioxidants work against each other. The whole take-antioxidants-for-better-health idea, which has been taking some hits in recent years, has just taken another big one.

To me, this suggests that nutrition is not simply the vitamins that we know about. After eating an orange, there are dozens of orange-specific and health-promoting compounds flowing around our bodies, not just vitamin C.

An interesting follow-up experiment would be to repeat this experiment but instead of 1000 mg of vitamin C and 400 IU of vitamin E, participants were to eat an additional two oranges and a handful of almonds. The additional "vitamin" intake would be about the same. If this were found to reduce the health benefits of exercise, then we'd really have to rethink nutrition.

Because alpha lipoic acid acts not as an "antioxidant" but as an activator of PGC-1a which in turn activates PPAR1gamma. "antioxidant" is just a label some people attach to every second molecule.
see alsohttp://www.ncbi.nlm.nih.gov/pubmed/18789599

I don't really think the study's authors can claim that anti-oxidant vitamins reduce the effects of exercise. They only tested vitamin supplements vs no supplement. To demonstrate what they want to demonstrate, they'd need to compare a diet with elevated anti-oxidant levels with vitamin supplements and an unchanged diet. If an "average" diet is better than both supplements and high nutrient foods, then they have proven that anti-oxidant regimes are harmful. It needs to be a comparative effectiveness study because otherwise you can run into placebo effect issues when comparing a diet study vs a a supplement study.

Without, all they've shown is that vitamin supplements are harmful in this case.

the next experiment should be exercise plus/minus artemesinin, which induces oxidative stress (and has been shown to be well tolerated in humans). Maybe add an arm that is plus/minus vitamins if you can afford it.
Barry

Unless the traffic fatalities are all pedestrians or the figures were counting fatalities at NASCAR, F1 races, or Le Mans, or unless your version of driving involves a whole lot more exercise than I am used to while driving, I don't think the above actually contradicts the "Mexican lemon imports/auto safety" hypothesis.

I'm wondering if this will spawn a whole new class of Vitamin C-related science fair experiments.

I donâ€™t know why the tow of you claim the study is flawed because it ignored dietary forms of the anti-oxidants? One mega vitamin has 10X the amount of Vitamin C as an orange. Except for saturable uptake at high doses there is no difference in ADME properties of synthetic and natural vitamin C, which tells me the body considers them the same. I find this study solid.

if supplements (vit C pills) are the same as food (multiple oranges), saying that the supplements reduce the benefits of exercise is the same as saying food reduces the benefits of exercise. really? is it the consistancy of the intake that's a problem vs. a couple oranges every couple days?

Oh this is precious. I've been pissed off for so long at the supplements people because of the lack of scientific support for their claims of a need for more antioxidants than you get in your diet and maybe a multivitamin (and it isn't like no one has been looking). Then it turns out that there actually is an effect and it runs counter to their claims!

The whole take-extra-antioxidants was based on the fact that people who had full diets with greens and proteins and so on had better health than people who lived off refined carbs and fat. Then some clever doctors figured that since scurvy was bad and vitamin C was present in greens and fruit and was an antioxidant then antioxidants must be essential for human health. Never mind that our blood is so packed with antioxidants that they crystallize out in our joints and kidneys. I hate doctors ;)

1. If Vitamin C is bad, does this mean I do not need collagen, cartilage, muscle and blood vessels? Because I was pretty sure the body uses Vitamin C to form all that.

2. Poor study design. I believe some points were already made.

3.Does Lance Armstrong take Vitamin C? I am very curious about him taking Vitamin C, because I am sure he won the Tour de France seven (7) times, and if you did not know, the Tour de France is an endurance sport.

Four groups of ten people. Sorry, but that raises a huge red flag. Statistically, this group was too small to draw reliable conclusions from, so the entire study is flawed. Come back when you have four groups of 100, or four groups of 1000, or even better yet, four groups of 100,000.

Remember the Woody Allen movie Sleeper?
Dr. Melik: This morning for breakfast he requested something called "wheat germ, organic honey and tiger's milk."
Dr. Aragon: [chuckling] Oh, yes. Those are the charmed substances that some years ago were thought to contain life-preserving properties.
Dr. Melik: You mean there was no deep fat? No steak or cream pies or... hot fudge?
Dr. Aragon: Those were thought to be unhealthy... precisely the opposite of what we now know to be true.
Dr. Melik: Incredible.

All this says is that one kind of thing that's good for you reduces the effect of another thing that's good for you. There's a million trade-offs like this. Get a larger sample and a longer study if you want to find out something potentially usfeful.

I mean, does anyone really think more oxidative stress could be good for you, long-term? Mitochondrial replication error won't show up for a very long time, but ultimately it kills you.

40 adults doesn't seem like a large enough sample size for conclusive results to eliminate sampling error. It means 20 were in each category of fitness and ten in each group were in the supplemented/nonsupplemeted categories. Fitness level is hardly an exact science, and variations of fitness capacity in people would not be accounted for in such a small sample size with no mention of how the individuals were determined to be athletic or not previously.

Also, I am not convinced that fitness level is as boolean as the study suggests. How was improvement in endurance measured? As a long distance runner I can tell you that my times vary from one day to the next and it's impossible to determine what single factor affects this variation. My previous post was in error because I assumed that half would be a control group that did not exercise, but I see that all participants exercised in this study.

The PNAS paper does not tell the whole story concerning antioxidants and insulin sensitivity:

In a new study antioxidant supplementation resulted in a significant reduction in oxidative stress while INCREASING insulin sensitivity and decreasing blood levels of chemicals associated with a risk of diabetes Read about it here:

In this randomized, double-blind, controlled trial, 48 overweight, and normal-weight, young adults received an antioxidant cocktail containing vitamin E (800 IU), (vitamin C (500 mg.), and beta-carotene (10 mg.), or placebo, for eight weeks. Endothelial adhesion molecules, lipid peroxidation, insulin resistance, and adiponectin were assessed at the start of the study and again after eight weeks. At the study's onset, overweight individuals exhibited greater insulin resistance and higher levels of endothelial adhesion molecules, which have been implicated in the developement of diabetes and atherosclerosis.

After eight weeks the overweight individuals experienced increased insulin sensitivity and decreased levels of endothelial adhesion molecules. Also their oxidative stress decreased and adiponectin levels increased. Higher levels of adiponectin are associated with a reduced risk of diabetes and cardiovascular disease.

Don't expect to read about this study in the pharma-sponsored MSM. They publish only articles which portay dietary supplements as worthless and/or harmful.

This paper's key methodological omissions (e.g., specification and reliable measures of each subject's baseline "training" and day-to-day treatment condition exercise "intensity") combine with its concealment of all individual subject size effects in powerless small N statistics, and its glaringly unqualified, provocative conclusion, to disqualify it from credible peer review (which, of course, no invited member of the NAS need submit to for PNAS "direct publication").

Nevertheless, at least this open access paper shows us the mean BMI of the "already athletically trained" and "untrained" groups -- a less than "healthy" statistical dead heat!

You could certainly see your skills within the paintings you write. The sector hopes for even more passionate writers like you who are not afraid to say how they believe. Always follow your heart. "Experience is a good school, but the fees are high." by Heinrich Heine.

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